Tolerance to alloantigens remains the single most important issue in marrow transplantation. The overall objectives of this program project are the following: 1) to develop novel strategies for influencing the induction of tolerance in bone marrow transplant (BMT) recipients; 2) to test potential interventions which selectively modulate the host and donor immune response to alloantigens; and 3) to apply the most promising interventions to human in utero and ex utero BMT. Engraftment tolerance will be studied in in utero transplant experiments in which the fetal recipient is relatively immunoincompetent. GVHD tolerance will be studied in patients who are recipients of haplocompatible T-cell depleted BMT. The studies to be conducted include the following: 1) development of anti-sense RNA molecules to induce down regulation of HLA expression; 2) measurement of soluble HLA antigens in patients undergoing BMT and the development of synthetic peptides which can block T-cell mediated cytoxicity 3) development of in vivo interventions in a murine model which can expand the time in gestation when the fetus is susceptible to engraftment of allogeneic cells; 4) characterization of a nonhuman primate model of in utero BMT which will assess the effect of anti T-cell monoclonal antibody in enhancing engraftment of mismatched marrow cells; 5) assessment of tolerance and immune reconstitution in patients undergoing haplocompatible BMT for severe combined immunodeficiency disease (SCID) or leukemia and the assessment of the efficacy of in utero BMT for children with hemoglobinopathies and SCID. These studies will substantially increase the number of patients who could benefit from BMT, and reduce the morbidity, mortality and the cost of marrow transplantation as well as impact on transplantation of solid tissue grafts.